Engineered Peptide Self-Assembled Nanofibers for Enhanced STING Activation: A Promising Nanodelivery Platform for Immunotherapy of Pediatric Solid Tumors.
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STING agonists (e.g., cGAMP), which function as immunotherapeutic agents activating the stimulator of interferon genes (STING) pathway, hold promise for treating pediatric solid tumors including neuroblastoma. However, their clinical translation is hindered by limitations including burst release, short half-life, poor targeting, and low intracellular delivery efficiency. In this study, we engineered a peptide self-assembled nanofiber (NFSA) based on the specific interaction mechanism between STING protein and cGAMP. By hydrophobically modifying the cGAMP-binding amino acid sequences on STING, two amphiphilic peptides, MP1 and MP2, were obtained, which self-assembled into nanofibers to efficiently encapsulate cGAMP. The NFSA showed excellent biocompatibility and low toxicity both in vitro and in vivo. It enabled pH-responsive cGAMP release, promoted cellular uptake, enhanced the endoplasmic reticulum (ER) localization, and activated the STING pathway. NFSA also promoted dendritic cell maturation and shifted tumor-associated macrophages to the anti-tumor M1 type. In vivo, NFSA reduced neuroblastoma growth, increased CD8+ T cell infiltration, induced tumor cell apoptosis, and demonstrated good biosafety. Our study developed a novel, easily producible, and low-toxicity STING agonist nanodelivery platform, which effectively overcomes key pharmacokinetic and pharmacodynamic barriers limiting clinical translation and provides a new strategy for efficient STING agonist delivery and immunotherapy of pediatric solid tumors.